Inflammatory dermatoses describe a group of diseases involving the layers of skin below the epidermis that have an inflammatory component. Inflammation may be triggered by a number of external events ranging from exposure to UV light from the sun to an allergen. Thalidomide has been demonstrated to have an inhibitory effect on the pro-inflammatory cytokines. It has been shown to inhibit TNF-alpha production in erythema nodosum leprosum patients (Sarno et al., Clin. Exp. Immunol, 84:103-8, 1991) and in vitro stimulated monocytes (Sampaio et al., J. Exp. Med., 173:699-703, 1991). Moreira et al. (J. Exp. Med., 177:1675-80, 1993) reported that thalidomide acts by enhancing TNF-alpha m-RNA degradation. Shannon et al. (Amer. Society for Microbiology Ann. Mtg., Abs. U-53, 1990) indicated thalidomide inhibited IL-1 beta production in vitro. Such an inhibitory effect on IL-1 beta may be direct or indirect through TNF-alpha as suggested by Moreira et al. (1993).
IL-1 beta and TNF-alpha are important factors in induction of endothelial cell-leukocyte receptors during inflammation, such as E-selectin (Bevilacqua et al., Science, 243:1160-65, 1989) VCAM 1 (Elices et al., Cell, 60:577-84, 1990) and ICAM (Rothlein et al., J. Immunol, 137:1270-4, 1986), in vitro and in the dermal vasculature in vivo. Expression of cellular receptors on the surface of endothelial cells facilitates the binding of inflammatory cells that is a precondition to transendothelial migration occurring during inflammation. Thalidomide also has an anti-angiogenic effect since TNF-alpha stimulates endothelial cell motility in vitro (Leibovich, Nature, 329:630-32, 1987; Rosen et al., In: Cell Mtility Factors Goldberg, I, and Rosen E. M., Editors, Birkhauser-Verlag, Basel, pg. 194-205, 1991 ) and has strong angiogenic activity in vivo (Leibovich et al., 1987; Frater-Schroder et al., Proc. Natl. Acad. Sci. (USA), 84:5277-5291, 1987). D'Amato et al. (Proc. Natl. Acad. Sci. (USA), 91:4082-5,1994) showed that thalidomide was an effective inhibitor of angiogenesis induced by bFGF.
In 1965 Sheskin (Lepr. Rev., 36:183-7) administered thalidomide to leprosy patients suffering from the complication erythema nodosum leprosum (ENL), to sedate them. ENL is characterized by recurrent erythematosus nodules on the skin, weight loss, mania, neuritis, fever, malaise, and sometimes epididyo-orchitis. Within 12 hours of thalidomide administration nodular eruptions began to heal and within two days fever declined and the ENL lesions had completely resolved. In 1971 lyer et al., Bull. WHO, 45:719-32, presented the results of a double blind clinical trial conducted in four countries and coordinated by the World Health Organization, which tested the efficacy of thalidomide versus aspirin for treatment of ENL. The conclusions reached supported Sheskin's original observations about the effectiveness of thalidomide for treatment of ENL. Wemambu et al. (Lancet, 2:933-5, 1969) observed necrotizing vasculitis of veins and arteries in patients with ENL. This was accompanied by initial neutrophil accumulation at disease sites as well as deposits of complement and immunoglobulin. This description of the disease process in ENL is consistent with that of an Arthus Reaction. However, others in the field disputed this explanation for ENL pathogenesis. Goihman-Yahr et al., Int. Arch. Allergy Appl. Immun., 57:317-332 (1978) showed in a study of neutrophil activation in ENL patients just before and during treatment with thalidomide that tissue damage was not due solely to neutrophil activation as occurs in immune complex diseases, but rather neutrophils appeared to be activated by an undefined lymphokine. This group went on to state that the therapeutic effect of thalidomide was not due to inhibition of neutrophil activation. Sarno et al. (Clin. Exp. Immunol., 84:103-8, 1991) showed that TNF-alpha levels were elevated in ENL patients and that TNF-alpha had a major role in the pathogenesis of this disease. Thalidomide was shown to inhibit TNF-alpha production in these ENL patients. Sampaio et al. (J. Inf. Dis., 168:408-14, 1993) confirmed Sarno's results as to the inhibitory effect of thalidbmide on serum TNF-alpha levels, but also demonstrated a reduction of dermal infiltration of polymorphonuclear leukocytes and T cells.
The fortuitous finding that thalidomide was effective in treating ENL stimulated other investigators to look at the efficacy of thalidomide for treating other dermatoses with a possible inflammatory and/or autoimmune pathogenesis.
Actinic prurigo is an inherited dermatological condition which afflicts 1-2% of the America Indian population. It often develops before puberty and presents initially as persistent eczematous eruptions on the face and other sun exposed areas. Later it spreads to sun protected areas of the body. Its etiology is unknown. Londono (Int. J. Dermatol., 12:326-8, 1973) was the first to report using thalidomide as a treatment for actinic prurigo. He administered 300 mg of thalidomide per day to 34 patients until clinical improvement was noted and then reduced the dosage progressively. There was notable improvement in 32 of the 34 patients, however, it took up to several months for clinical improvement to occur as compared to the short period of time it took for complete resolution of ENL lesions. Londono postulated it had an immunological etiology. Lovell et al. (Brit. J. Dermatol, 108:467-71, 1983) treated 14 actinic prurigo patients with 50-100 mg of thalidomide per day for children and 100-200 mg of thalidomide per day for adults, for variable periods of time. Eleven patients had long term clinical improvement and three were free of symptoms even after thalidomide was discontinued. No side effects were noted.
Prurigo nodularis is a dermatological condition characterized by excoriated and hyperpigmented dome shaped nodules. Lesions are extremely pruritic and maybe triggered by exposure to sunlight or insect bites or may be idiopathic in nature. Results of skin biopsies for this condition are indicative of chronic dermatitis or lichen simplex chronicums. Diagnosis is made on the basis of clinical criteria. Mattos (Bol. Div. Nac. Lepra., 32:71) in 1973 was the first investigator to use thalidomide to treat prurigo nodularis. One of the two patients treated received 200 mg per day of thalidomide and the other patient, a woman, received 300 mg daily. Both patients had excellent clinical responses to the therapy after several weeks. Sheskin (Hautarzt, 26:215, 1975) reported treating three prurigo nodularis patients with thalidomide. These patients suffered from the disease for eight to twenty-four years, but responded clinically within a few weeks of initiation of thalidomide therapy. Other studies (Van den Broek, Arch. Dermatol, 116:571, 1980; Nikolowski, Hautarzt, 31:565, 1980; Winkelmann et al., Acta. Dermato-Venereologica, 64:412-7, 1984) have confirmed this clinical improvement in patients, with the intensive itch that accompanies this condition subsiding within 2-3 weeks of the start of 200 mg per day of thalidomide. However, in these studies it was noted that it takes at least six months of thalidomide therapy before strongly lichenified lesions completely heal.
Discold lupus erythematosus is a chronic recurrent skin infection predominantly afflicting women. Skin lesions consist of red macules that are covered with scales and extend into follicles. Lesions are characteristically distributed in a butterfly pattern across the cheeks and bridge of the nose, but may occur in other body areas as well. The disease is believed to have an autoimmune etiology. The disease may be induced by administration of certain drugs. Barba-Rubio and Gonzalez, Derm. Rev. Mex., 19:131 (1975) treated 20 discold lupus erythematosus patients with 300 mg of thalidomide per day. Within two weeks 19 of these patients responded clinically and the medication was then reduced to a maintenance dose of 25 mg per day. Other groups (Knop et al., Arch. Dermatol. Res., 271:165-70, 1983; Levi et al., Giorn. Ital. Derre. Vener, 115:471, 1980; Samsoen et al., Ann. Dermatol Venereol (Paris), 107:515-23, 1980) confirmed the effectiveness of thalidomide therapy in treating discold lupus erythematosus patients refractory to other treatments such as steroids. In most instances a clinical effect was detected within 14 days of initiation of 100-200 mg per day of thalidomide, however, a total and definite recovery was seen in only 15-20% of patients. In most patients a 25-50 mg per day maintenance dose of thalidomide was required to sustain a clinical improvement.
Thalidomide has also been used successfully to treat Behcet's syndrome, a rare and severe illness of unknown etiology often afflicting young males. It is characterized by progressive ulceration of the mouth and genitalia, uveitis, and retinal vasculitis. There also may be atrophy of the gastrointestinal tract and pulmonary or myocardial fibrosis. Thalidomide therapy was an important breakthrough, because prior to this there was no specific treatment for Behcet's syndrome. Steroids proved to be only of limited usefulness in treating Behcet's and only symptomatic or supportive measures were being prescribed (Mamo et al., Arch. Ophthamol, 71:4-14, 1964). Saylan and Saltik (Arch. Dermatol, 118:536, 1982) were the first to use thalidomide to treat 22 patients with Behcet's syndrome who had deep and persistent oral aphthae. Patients were initially administered 400 mg per day of thalidomide for five days followed by 200 mg per day for 15 to 60 days. This regimen resulted in rapid and complete healing of aphthae. Torras et al. (Arch. Dermatol, 118:875, 1982) found that there was complete healing of giant aphthae in eight of nine Behcet's patients treated with 100 mg per day of thalidomide for 10 days. Jorizzo et al. (Arch. Int. Med., 146:878-81, 1986) reported similar success with thalidomide in five patients with Behcet's syndrome. In 1993 Denman et al., Rev. Med. Int., 14:(suppl 1) 495, treated 39 patients with Behcet's syndrome with 50 mg of thalidomide three nights per week for a mean time of 35.9 months and a maximum treatment time of up to 65 months. Concomitant treatment in this patient group included 10 patients on prednisone, 3 on azathioprine and 1 patient on cyclosporin. Mucosal lesions healed in all patients. Moulin et al. (Ann. Dermatol Venereol, 110:611, 1983) used 100 mg per day of thalidomide to treat six patients with a Jessner-Kanof lymphocytic infiltration of the skin. This disease is characterized by numerous lesions on the face and back with lymphocytic infiltration of the dermis, but little modification of the epidermis. In five of the six patients there was clinical improvement in skin lesions, however, most patients relapsed if treatment was stopped. A 25-50 mg per day maintenance regimen helped three of the five patients to maintain normal skin over two years. Eravelly and Waters, Lancet, i:251 (1977) treated a patient with a relapsing non-suppurative panniculitis termed Weber Christian Disease, with 300 mg per day of thalidomide for three weeks which was reduced to 200 mg per day and then to 100 mg per day after 10 days. Therapy was stopped after 13 weeks. The patient's skin lesions steadily regressed during therapy and it was reported that a disease free state was maintained for 13 months after thalidomide was stopped. Thalidomide has also been used to treat recurrent erythema multiforme, a flu like syndrome in which blisters appear on mucous membranes of the mouth followed by lesions on the hands and feet. Corticosteroids are used to treat severe forms of the condition, however, the side effects of this therapy detract significantly from its advantages. Bahmer et al., Acta. Derm. Venereal, 62:449 (1982) treated a patient who had recurrent erythema multiforme with 200 mg of thalidomide per day. Within a few days the mucosal membrane and skin lesions healed and the daily dosage of thalidomide was lowered. The patient has been maintained in a disease free state by administration of 100 mg of thalidomide per day.
As indicated oral administration of thalidomide has been successfully used to treat a limited number of dermatoses that may have an autoimmune and/or inflammatory component associated with them. Topical application of thalidomide is a useful therapeutic approach for disease states with an autoimmune and/or inflammatory basis. Furthermore, thalidomide may be used alone to treat dermatoses with an autoimmune and/or inflammatory basis or in unique combinations with other cytokine/growth factor inhibitors and/or other anti-inflammatory and/or anti auto-immune agents and/or other physical and/or chemical dermatological treatments. An example of such combination therapy could involve thalidomide given with pentoxifylline and a glucocorticoid such as dexamethasone. The activity of each of these agents would be expected to enhance that of the other two in inhibiting TNF-alpha synthesis since each of these agents acts as an inhibitor at a different point in this synthesis. Pentoxifylline inhibits TNF-alpha gene transcription (Doherty et al., Surgery (St. Louis), 110:192, 1991), while thalidomide enhances TNF-alpha m-RNA degradation (Moreira et al., 1993) and glucocorticoids such as dexamethasone inhibit TNF-alpha m-RNA translation (Han et al., J. Exp. Med., 172:391, 1990).
Thalidomide has been administered orally, however, it may be used topically to treat dermatoses with an autoimmune and/or inflammatory component associated with them, such as, for example, using creams, ointments or lotions or in combination with other therapies.
Thalidomide was first synthesized and marketed in the 1950's as a sedative. The toxicity of the compound was so low that a dose killing 50% of animals (LD.sub.50) could not be established. Thalidomide was therefore thought to be a safer alternative to barbiturates. In 1961 thalidomide administered to pregnant women resulted in an epidemic of congenital malformation. The incidence of malformed babies paralleled the sales of thalidomide and quickly dropped off when thalidomide was removed from the market.
Oral administration of thalidomide in the range of 100-200 mg in adult humans results in a peak blood level of 0.9-1.5 mg/liter after 4-6 hours. Hydrolytic cleavage of thalidomide occurs in vitro, the rate of which increases as the pH increases. However, hydrolytic cleavage of thalidomide in serum is much slower than in vitro at pH 7.4. This may be due to thalidomide being highly bound to plasma proteins. Studies in animals demonstrated high thalidomide concentrations in the gastrointestinal tract, liver and kidneys with lower concentrations in muscle, brain and adipose tissue. In pregnant animals, thalidomide can pass across the placenta.
Although a complete study of thalidomide metabolism in humans has not been performed, in animals the main pathway for thalidomide breakdown appears to be nonenzymatic hydrolytic cleavage. Even though immunomodulatory effects of thalidomide have not been clearly defined at the molecular level, thalidomide has been used to treat the following immunologically-based diseases: acute aphthous ulcers (Jenkins et al., Lancet, 2:1424-6, 1984; Grinspan, J. Amer. Acad. Dermatol, 12:85-90, 1985; Revuz et al., Arch. Dermatol, 126:923-7, 1990), graft vs host disease (Lim et al., Lancet, 1:117, 1988; McCarthy et al., Lancet, 2:1135, 1988; Henley et al., Lancet, 2:1317, 1988), erythema nodosum leprosum (Sheskin, Lepr. Rev., 36:183-7, 1965; Sheskin and Convit, Int. J. Lerp., 37:135-46, 1969; Pearson and Vedagirl, Lepr. Rev., 40:111-16, 1969), Behcet's syndrome (Saylan and Saltik, 1982; Jorizzo et al., Arch. Int. Med., 146:878-81, 1986), actinic prurigo (Londono, Int. J. Dermatol, 12:326-8, 1973; Lowell et al., 1983), ulcerative colitis (Waters et al., Brit. Med. J., 1:792, 1979) and discold lupus erythematosus (Knop et al., Arch. Dermatol Res., 271:165-70, 1981). In these studies, dosages of thalidomide ranging from 100 mg/day to 800 mg/day were administered without serious side effects.